tbuckley/cabot-search huggingface dataset:
PATH-03. Clinically Tractable Outcome Prediction of Group 3/4 Medulloblastoma Based on TPD52 Immunohistochemistry: a Multicohort Study
Authors: Alberto Delaidelli, Christopher Dunham, Mariarita Santi, Gian Luca Negri, Joanna Triscott, Olga Zheludkova, Andrey Golanov, Marina Ryzhova, Konstantin Okonechnikov, Daniel Schrimpf, Damian Stichel, David Ellison, Andreas von Deimling, Marcel Kool, Stefan Pfister, Vijay Ramaswamy, Michael Taylor, Andrey Korshunov, Poul Sorensen
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: International consensus and the 2021 WHO classification recognize eight molecular subgroups among Group 3/4 medulloblastoma (representing ~60% of medulloblastoma). However, very few clinical centers worldwide possess the technical capabilities to determine DNA-methylation patterns or other molecular parameters of high-risk for Group 3/4 tumors. As a result, biomarker-driven risk stratification and therapy assignment constitutes a major challenge in medulloblastoma research. Here, we identify an immunohistochemistry (IHC) marker as a clinically tractable method for improved medulloblastoma risk-stratification. PATIENTS and METHODS: We bioinformatically analyzed published medulloblastoma transcriptomes and proteomes identifying as a potential biomarker TPD52, whose IHC prognostic value was validated across three Group 3/4 medulloblastoma clinical cohorts (n = 387) treated with conventional therapies. Risk stratification and prediction capability were computed utilizing uni- and multivariate survival analysis. Newly developed risk classifiers including TPD52 IHC were compared to state-of-the-art risk stratification schemes in terms of prediction error, area under the time-dependent receiver operating characteristic (ROC) curves and C-statistic. RESULTS: TPD52 IHC percentage positivity represents a significant independent predictor of early relapse and death for Group 3/4 medulloblastoma (HRs between 3.67-26.7 [95% CIs between 1.00-706.23], p = 0.05, 0.017 and 0.0058). Cross-validated survival models incorporating TPD52 IHC with clinical and molecular features (subgroup affiliation, MYC status) outperformed existing disease risk-stratification schemes, and reclassified ~50% of patients into more appropriate risk categories. Finally, interaction effect in multivariate analyses revealed that TPD52 immunopositivity could be a predictive indicator of poor response to chemotherapy (HR 12.66 [95% CI 3.53-45.40], p &amp;lt; 0.0001), suggesting important implication for therapeutic choices. CONCLUSION: The current study adds an important asset to improve risk-stratification for Group 3/4 medulloblastoma. Integration of TPD52 IHC in classification algorithms significantly improves outcome prediction and can be rapidly adopted for risk stratification on a global scale, independently of advanced but technically challenging molecular profiling techniques.
Bite-on-bite biopsies for the detection of residual esophageal cancer after neoadjuvant chemoradiotherapy
Authors: Ruben D. van der Bogt, Berend J. van der Wilk, Lindsey Oudijk, Erik J. Schoon, Gesina van Lijnschoten, Sietske Corporaal, Judith Nieken, Peter D. Siersema, Tanya M. Bisseling, Rachel S. van der Post, Rutger Quispel, Arjan van Tilburg, Liekele E. Oostenbrug, Robert G. Riedl, Lieke Hol, Mike Kliffen, Suzan Nikkessen, Ben M. Eyck, J. Jan B. van Lanschot, Michael Doukas, Manon C. W. Spaander
Journal: Endoscopy (2022)

Background Active surveillance after neoadjuvant treatment is increasingly implemented. The success of this strategy relies on the accurate detection of residual cancer. This study aimed to assess the diagnostic value of a second (bite-on-bite) biopsy for the detection of residual esophageal cancer and to correlate outcomes to the distribution of residual cancer found in the resection specimen. Methods A multicenter prospective study of esophageal cancer patients undergoing active surveillance after neoadjuvant chemoradiotherapy was performed. At clinical response evaluations, an upper gastrointestinal (GI) endoscopy was performed with at least four bite-on-bite biopsies of the primary tumor site. First and second biopsies were analyzed separately. Patients with histopathological evidence of residual cancer were included in the primary analysis. Two pathologists blinded for biopsy outcome examined all resection specimens. Results Between October 2017 and July 2020, 626 upper GI endoscopies were performed in 367 patients. Of 138 patients with residual cancer, 112 patients (81 %) had at least one positive biopsy. In 14 patients (10 %) only the first biopsy was positive and in 25 patients (18 %) only the second biopsy (P = 0.11). Remarkably, the rates of patients with tumor-free mucosa and deeper located tumors were higher in patients detected by the first biopsy. The second biopsy increased the false-positive rate by 3 percentage points. No adverse events occurred. Conclusions A second (bite-on-bite) biopsy improves the detection of residual esophageal cancer by almost 20 percentage points, at the expense of increasing the false-positive rate by 3 percentage points. The higher detection rate is explained by the higher number of biopsies obtained rather than by the penetration depth.
Does hyponatremia predict worse outcomes in gastric cancer?: A nationwide study.
Authors: Jorge Franco, Diana Franco, Umer Farooq, Irene Ma
Journal: Journal of Clinical Oncology (2022)

e16098 Background: Hyponatremia has historically been reported to increase mortality and length of stay in hospitalized patients with solid tumors. There are sparse reports of hyponatremia linked to gastric cancer in the published literature. Therefore, we evaluated mortality, morbidity, and resource utilization in gastric cancer patients secondary to hyponatremia. Methods: We investigated the National Inpatient Sample 2019 employing International Classification of Diseases-10 (ICD-10) codes to include adult patients with gastric cancer. Effect of hyponatremia was studied on mortality, morbidity, and resource utilization. Analyses were performed using STATA (v 14.2), considering 2 sided P&lt; 0.05 as statistically significant. Proportions were compared using Fisher exact test and continuous variables using Student’s t-test. Confounding variables were adjusted using multivariate logistic and linear regression analyses. These included: gender, race, Charlson Comorbidity Index, chronic kidney disease, congestive heart failure, cirrhosis, nephrotic syndrome, hypothyroidism, adrenal insufficiency, alcohol use disorder, and admission for hypovolemia or psychogenic polydipsia and various patient and hospital characteristics. Results: Out of 43,015 patients with gastric cancer in 2019, 13.59% (5,845) had hyponatremia on presentation (Table. 1). Patients with hyponatremia had 12.23% in-hospital mortality, while 6.69% for patients without hyponatremia. After adjusting for confounders, hyponatremia imparted higher odds of mortality (Adjusted odds ratio (aOR) for mortality 1.89, 95% confidence interval (CI): 1.54–2.32, P&lt; 0.01). Hyponatremia also resulted in higher resource utilization marked by the length of stay, hospital charges, and ICU admission (higher mean LOS by 2.09 days, higher mean total hospital charges by $22,320, and higher odds of ICU admission). In addition, patients with hyponatremia had higher odds of acute renal failure (aOR 2.38, 95% CI: 2.05–2.77, P&lt; 0.01). Rates of cerebral edema and altered mental status were equal between the two study groups ( P&gt; 0.05). Conclusions: Hyponatremia in gastric cancer patients had a prevalence of 13.59% and resulted in increased in-hospital mortality. Whether time-efficient treatment of hyponatremia would help reduce mortality and improve outcomes remains to be determined in future studies.[Table: see text]
Ensuring equal access: Language as exclusion criteria among clinical trials in gynecologic oncology.
Authors: Sarah S. Lee, Andreea Dinicu, Likolani Arthurs, Danielle Seda, Bhavana Pothuri, Michelle DS Lightfoot
Journal: Journal of Clinical Oncology (2022)

e18587 Background: Enrolling a diverse patient population into clinical trials may help mitigate disparities and ensure generalizability of results. We aimed to assess clinical trial eligibility criteria that may adversely impact enrollment of underrepresented groups. Methods: We searched clinicaltrials.gov for gynecologic cancer studies between 1997 and 2021. Studies were excluded if they included non-gynecologic or multiple sites of disease; hereditary gynecologic cancer syndromes were included. The inclusion and exclusion criteria of each study were reviewed to determine if demographic factors were used for enrollment screening. Our outcome of interest was the characterization of inclusion and exclusion factors that may adversely impact enrollment of historically underrepresented groups. Data were analyzed using chi-square tests, logistic regression, and Cochrane-Armitage test of trends. Results: A total of 1614 studies were included; 902 (56%) were ovarian, 357 (22%) were cervical, and 355 (22%) were uterine cancer studies. The majority (86%, n = 1394) were therapeutic trials, 38% (n = 608) were phase 2, and 8% (n = 123) were phase 3. Ovarian cancer trials were most likely to be industry-sponsored (252, 28%), compared to only 12% of cervical and endometrial cancers (n = 44 each, p &lt; 0.001). Overall, 190 gynecologic cancer studies (12%, n = 190) excluded patients based on language. Cervical cancer studies were the most likely to exclude patients based on language (n = 67, 19%), compared to endometrial cancer (n = 45, 13%) and ovarian cancer (n = 78, 9%, p &lt; 0.001). Compared to investigator-initiated trials, industry-sponsored trials (adjusted OR [aOR] 0.07, 95% confidence interval [CI] 0.02-0.29) and organizational/government-sponsored trials (aOR 0.37, CI 0.21-0.66) were less likely to exclude based on language. Compared to drug/device trials, behavior/quality of life studies (aOR 31.63, CI 18.50-54.09) and prevention/diagnosis trials (aOR 5.14, 2.81-9.41) were more likely to exclude based on language. During the study period, the number of studies using language as exclusion criteria increased over time (p &lt; 0.001). Conclusions: Over the last three decades, one in ten gynecologic cancer trials excluded patients based on language. Studies focused on cervical cancer, investigator-initiated, and behavior/quality of life studies were most likely to exclude on the basis of language. Eliminating language as an exclusion criterion in clinical trial eligibility could improve understanding of the health-related quality of life among all patients with gynecologic cancer and help achieve equity in clinical trial enrollment.
Interrogating the Significance of PARP1 Expression and PBRM1 Mutation as Biomarkers for Predicting the Response to Atezolizumab plus Bevacizumab or to Sunitinib in Patients with Clear Cell Renal Cell Carcinoma
Authors: Javier Lanillos, María Santos, Carlos Valdivia, Alberto Mora, Cristina Rodríguez-Antona
Journal: European Urology (2022)
Excess of blood TNFa-R as a sign of recurrence of G1 soft tissue sarcomas in older men and G3 soft tissue sarcomas in older women.
Authors: Irina V. Kaplieva, Susan A. Sagatelyan, Elena M. Frantsiyants, Larisa N. Vashchenko, Irina A. Goroshinskaya, Tatiana V. Ausheva, Pavel V. Chernogorov, Yulia A. Pogorelova, Elena A. Sheiko, Ludmila A. Nemashkalova, Marina A. Gusareva, Elizaveta V. Serdyukova, Oksana V. Bykadorova, Dmitriy P. Atmachidi, Andrey A. Maslov, Oleg I. Kit
Journal: Journal of Clinical Oncology (2022)

11556 Background: Tumor necrosis factor alpha (TNFa) and its receptor (TNFa-R) play an important role in tumor genesis. However, their involvement in the recurrence of sarcomas is poorly studied. The purpose of this study was to analyze levels of TNFa and TNFa-R in the blood of patients with recurrent soft tissue sarcomas. Methods: The study included 64 male and female patients, mean age 63.4±5.2 years. Main groups included patients with recurrent G1 and G3 soft tissue sarcomas T2bN0M0; comparison groups included patients with primary G1 and G3 soft tissue sarcomas T2bN0M0. 95% of tumors were liposarcomas, with solitary rhabdamyosarcomas, myxofibrosarcomas, epithelioid and undifferentiated sarcomas. All recurrent patients had previously underwent surgical and radiation treatment for primary sarcomas and their relapses (up to 2 episodes), with the last surgery more than 1 year ago. Control groups (n = 10 each) included healthy donors of similar age. Levels of TNFa and TNFa-R were measured in the blood serum by ELISA before the treatment. Results: No significant differences were found between TNFa levels in patients with primary and recurrent soft tissue sarcomas and in donors. Levels of TNFa-R in men with primary G3 sarcomas were 1.5 times (p &lt; 0.05) higher compared with donors, 1.7 times (p &lt; 0.05) higher than in men with primary G1 sarcomas, and 1.3 times (p &lt; 0.05) higher than in women with primary G3 sarcomas. TNFa-R increased by 1.7 times (p &lt; 0.05) in all men with recurrent sarcomas regardless of the tumor grade, compared with the levels in healthy men; however, in G1 it was 1.9 times (p &lt; 0.05) higher than in men with primary G1 sarcomas, while in G3 it did not differ significantly from the levels in men with primary G3 sarcomas. TNFa-R in women increased only in recurrent G3 sarcomas by 2.5 times compared to healthy women. No differences were observed in TNFa-R levels between men and women with recurrent G3 sarcomas. Conclusions: An excess of TNFa-R in the blood is characteristic for the recurrent soft tissue sarcomas G1 in older men and G3 in older women. At the same time, high grade tumors in men are accompanied by an increase in TNFa-R in the blood in both primary and recurrent sarcomas.
Methods used to generate safety-related evidence in real-world oncology settings: A systematic literature review.
Authors: Mackenzie Henderson, Jenilee Cueto, Priyanka Yalamanchili, Maribel Salas
Journal: Journal of Clinical Oncology (2022)

e18769 Background: With the increasing availability of real-world data (RWD) as a valuable healthcare data source, there have been large shifts in how a drug’s properties can be evaluated over its life cycle. RWD can be used for many evidence generation purposes, including the evaluation of a drug’s safety in real-world settings outside of clinical trials. Traditional methods (e.g., cohort and case-control studies) are often used to analyze RWD, but novel methods have emerged as the field advances with access to more diverse data sources. The extent to which these newer methods are being used is unclear. The aim of this systematic review is to identify methods that have been used in recent years to generate safety-related evidence in real-world oncology settings. Methods: A search of literature published between 1/1/2016-8/10/2021 (Embase, Ovid) was performed to identify studies describing methods used to generate evidence related to the real-world safety of oncology products. Each article was independently screened by two researchers in two levels (title/abstract and full text screening). Data extracted included, but was not limited to, study design, cancer type, data source, and statistical methods. Results: Out of 845 publications identified, 44 were included for review (742 excluded after level 1 screening; 59 excluded after level 2 screening). The most common method used was the retrospective cohort study (n = 26), followed by prospective cohort study (n = 8), literature review (n = 4), cross-sectional study (n = 3), artificial intelligence (AI) methods (n = 3), data mining analysis (n = 2), case-series, and case-control study (n = 1 each). Some publications used multiple methods. While traditional methods (e.g., cohort study, literature review) were the most common throughout the search period, newer methods (e.g., AI methods) were identified in the latter part of the search period (2019-2020). The majority of studies that used traditional methods relied on medical records or claims data (e.g., Optum), which often provided structured RWD to evaluate physician-documented drug safety data. In contrast, articles that used newer methods like AI analyzed large amounts of patient-reported data (e.g., chatbot conversations; social networks), which allowed researchers to evaluate patients’ own experiences with drug safety. Conclusions: The most common evidence generation methods identified involved traditional methods, but novel methods were also identified, especially in recent years. This indicates a trend towards increased use of innovative methods like AI that allow for the analysis of data in ways not possible before. Taken together with more traditional methods and data sources, these findings can provide clinicians with a more comprehensive and patient-focused understanding of drug safety, which will ultimately improve patient care.
The impact of BMI on the response to immunotherapy in lung cancer.
Authors: Yuan Ying, Veena Gujju, Gideon Hallum, Sufana Shikdar, Sara Vesely, Spencer Hall, Adanma Ayanambakkam, Raid Aljumaily
Journal: Journal of Clinical Oncology (2022)

e21003 Background: Over the past few years immunotherapy was incorporated in the first line treatment for advanced lung cancer. Obesity leads to a state of low grade chronic inflammation and plays a role in many pathophysiological processes including tumorigenesis. Recently evidence indicates that obesity and related inflammatory state may also impact the efficacy of immunotherapy. Methods: We conducted a retrospective study to look at the impact of body mass index (BMI) on the outcomes in patients with advanced lung cancer treated with immune check point inhibitors (ICI). According to their baseline BMI, patients were grouped into obese (BMI ≥ 30, n = 54) and non-obese (BMI &lt; 30, n = 158). In another comparison using 25 as BMI cut off, patients were grouped into higher BMI (BMI ≥ 25, n = 105) and lower BMI (BMI &lt; 25, n = 107). Results: From June 2012 to December 2020, 212 patients from our institute were included in this study. The median age was 64.5, average BMI was 26.4 kg/m 2 , and 52% male sex. Median follow-up time in this study was 21.7 months. Patients with higher BMI using 25 as cut off had longer progression free survival (PFS) (8.1 months vs 5.3 months, p = 0.0034). Overall survival (OS) was better in higher BMI group than lower BMI group (10.8 months vs 5.9 months, p = 0.0008). The differences of PFS and OS for obese and non-obese groups were not statistically different (11.1 months vs 5.9 months, p = 0.157 for PFS; 12.0 months vs 6.9 months, p = 0.1512 for OS.). Conclusions: Our results suggest that excess weight may be associated with favorable PFS and OS in advanced lung cancer patients treated with ICI. Future studies are needed to investigate the underlying mechanism of this association.
Transforming dysfunctional CD8+ T cells into natural controller–like CD8+ T cells: can TCF-1 be the magic wand?
Authors: Hiroshi Takata, Lydie Trautmann
Journal: Journal of Clinical Investigation (2022)

HIV infection results in defective CD8+ T cell functions that are incompletely resolved by antiretroviral therapy (ART) except in natural controllers, who have functional CD8+ T cells associated with viral control. In this issue of the JCI, Perdomo-Celis et al. demonstrated that targeting the Wnt/transcription factor T cell factor 1 (Wnt/TCF-1) pathway in dysfunctional CD8+ T cells led to gains in stemness phenotype, metabolic quiescence, survival potential, response to homeostatic γ-chain cytokines, and antiviral capacities, similar to profiles of functional CD8+ T cells in natural controllers. Although reprogramming might not sufficiently reverse the imprinted dysfunction of CD8+ T cells in HIV infection, these findings outline the Wnt/TCF-1 pathway as a potential target to reprogram dysfunctional CD8+ T cells in efforts to achieve HIV remission.
S1P/ceramides and cytokines as potential biomarkers of response following administration of bxq-350.
Authors: Gilles Tapolsky, Olivier Rixe, John Charles Morris, Robert Wesolowski, Emrullah Yilmaz, Anne M. Noonan, John L. Villano, Richard Charles Curry, Carolyn Muller, Trisha Michel Wise-Draper, Vinay K. Puduvalli, Ray Takigiku
Journal: Journal of Clinical Oncology (2022)

e15007 Background: BXQ-350 was investigated in a Phase 1 dose-escalation safety study of all-comer cancer patients with advanced solid malignancies, including high grade gliomas ( NCT02859857 ) (safety/efficacy results reported in a separate abstract). The primary objective of this single agent study was to describe the safety profile and to determine the maximum tolerated dose. Multiple secondary parameters were included to characterize BXQ-350’s pharmacokinetic parameters, efficacy profile and elucidation of potential biomarkers. BXQ-350 is a nanovesicle of recombinantly expressed Saposin C (SapC) and dioleoylphosphatidylserine. In nature, SapC is a protein encoded by the Psap gene, and serves as an allosteric activator of several enzymes involved in sphingolipid/ceramide metabolism, enzymes which are being investigated as novel therapeutic targets in cancers. Indeed, sphingolipids are a class of bioactive signaling molecules implicated in multiple cellular processes and molecular pathways. Amongst these sphingolipids, Sphingosine-1-Phosphate (S1P) induces cancer cell survival and proliferation, activates multiple oncogenic pathways, and promotes a pro-tumoral microenvironment. SapC has broad anticancer activity, lowering S1P and increasing ceramides, also inducing an anti-tumoral immune response. Methods: Lipodomic analysis (sphingolipids) and cytokines were analyzed in plasma samples of a subset of patients enrolled in this study. Results: Analysis of plasma biomarker samples, collected throughout the period patients were on study, reveals notable changes of circulating sphingolipids and cytokines. A subset of patients exhibited clinical benefits following BXQ-350 administration (see other presentation for details; ̃17% of the evaluable patients remained on study up to Cycle 6; and 8 patients (̃11%) with PFS&gt; 6 months). Concomitant circulating changes in S1P and other ceramides may be indicative of treatment effect. Also, concurrent changes in circulating levels of pro/antitumoral cytokines were noted. Conclusions: While these results are exploratory and preliminary in nature, these initial results warrant further investigation. These observations will be further explored in specific cancer and non-cancer indications. Clinical trial information: 02859857.